The autophagy scaffold protein ALFY is critical for the granulocytic differentiation of AML cells

Acute myeloid leukemia (AML) is a malignancy of myeloid progenitor cells that are blocked in differentiation. Acute promyelocytic leukemia (APL) is a rare form of AML, which generally presents with a t(15;17) translocation causing expression of the fusion protein PML-RARA. Pharmacological doses of a...

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Bibliographic Details
Published in:Scientific reports 2017-10, Vol.7 (1), p.12980-12, Article 12980
Main Authors: Schläfli, Anna M., Isakson, Pauline, Garattini, E., Simonsen, Anne, Tschan, Mario P.
Format: Article
Language:English
Subjects:
631/67/1990/283/1897
631/80/39/2346
Acute myeloid leukemia
Acute promyeloid leukemia
Autophagy
Chemotherapy
Fusion protein
Humanities and Social Sciences
Leukemia
Lysosomes
Macromolecules
Malignancy
mRNA
multidisciplinary
Myeloid leukemia
Phagocytosis
Progenitor cells
Promyeloid leukemia
Proteins
Proteolysis
Retinoic acid
Science
Science (multidisciplinary)
Stem cells
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Summary:Acute myeloid leukemia (AML) is a malignancy of myeloid progenitor cells that are blocked in differentiation. Acute promyelocytic leukemia (APL) is a rare form of AML, which generally presents with a t(15;17) translocation causing expression of the fusion protein PML-RARA. Pharmacological doses of all-trans retinoic acid (ATRA) induce granulocytic differentiation of APL cells leading to cure rates of >80% if combined with conventional chemotherapy. Autophagy is a lysosomal degradation pathway for the removal of cytoplasmic content and recycling of macromolecules. ATRA induces autophagy in ATRA-sensitive AML and APL cells and autophagy inhibition attenuates ATRA-triggered differentiation. In this study, we aimed at identifying if the autophagy-linked FYVE-domain containing protein (ALFY/WDFY3) is involved in autophagic degradation of protein aggregates contributes to ATRA therapy-induced autophagy. We found that ALFY mRNA levels increase significantly during the course of ATRA-induced differentiation of APL and AML cell lines. Importantly ALFY depletion impairs ATRA-triggered granulocytic differentiation of these cells. In agreement with its function in aggrephagy, knockdown of ALFY results in reduced ATRA-induced proteolysis. Our data further suggest that PML-RARα is an autophagy substrate degraded with the help of ALFY. In summary, we present a crucial role for ALFY in retinoid triggered maturation of AML cells.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-017-12734-4